Endpoint summary

Administrative data

Description of key information

Lactide (18:1 mixture of L-lactide and m-lactide) was tested in dogs in a 2 week dose range finding study and a subsequent 90d full study similar to OECD 408. The primary toxic effect was irritation of the gastrointestinal tract at 100 mg/kg/d in the 90d study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published study, meets generally accepted scientific standards and is described in sufficient detail

Doses for the 13-wk study were selected based on the results of a 2-week study. In the 13-wk study, four dogs per sex were assigned to each of four treatment groups (dosed with lactide at 0, 4, 20 and 100 mg/kg body weight/day). Each dog received daily oral doses of one to six gelatin capsules containing lactide. Doses were administered at approximately 1 hr after feed was withdrawn, and at approximately the same time each day for 13 weeks. Control dogs received the same number of empty capsules as dogs of the corresponding sex in the highest dose group. Doses were calculated based on the body weight of each dog during the previous week.

Each dog received daily oral doses of one to six gelatin capsules containing lactide. Doses were administered at approximately 1 hr after feed was withdrawn, and at approximately the same time each day for 13 weeks. Control dogs received the same number of empty capsules as dogs of the corresponding sex in the highest dose group. Doses were calculated based on the body weight of each dog during the previous week.

Observations:- Dogs were observed twice daily for mortality or moribundity. - Cageside observations were performed daily, approximately 1 hr after dosing. - Once a week, each dog was removed from its cage and examined closely for detailed clinical signs of toxicity. - Throughout each study:dogs were weighed weekly, and food consumption was measured once a week over a 2-hour period.

Clinical pathology:- blood and urine samples were obtained from each dog for clinical pathology and urinalysis determinations during quarantine, during week 5 and 9, and within 3 days prior to terminal sacrifice

- Groups means and standard deviations for: body weights, food consumption, clinical pathology parameters, for terminal body weights and for absolute and relative organ weights- Body weights, food consumption and clinical pathology parameters were evaluated by two-way repeated ANOVA, and if significant by Dunnett´s test- Mean body weights, mean organ weights and organ/body, organ:brain ratios for each treated group were compared to those of the control group by a two-tailed Students t-test for each sex

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Emesis once in each of two female dogs (one in the 0 mg/kg and one in the 100 mg/kg group during week 9). Bloody diarrhoea was seen once during week 6 in one female dog of the 100 mg/kg group

Mortality:

mortality observed, treatment-related

Description (incidence):

Emesis once in each of two female dogs (one in the 0 mg/kg and one in the 100 mg/kg group during week 9). Bloody diarrhoea was seen once during week 6 in one female dog of the 100 mg/kg group

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

stomach foci in one male/female from the 100 mg/kg , and one female from the 4mg/kg dose group

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

moderately severe ulceration of the stomach mucosa seen in one female dog of the high dose group

Incidence= number of dogs in a given dose group with a given lesion. n=4 for all dose groups

Conclusions:

Lactide acts primarily, if not only, as an irritant after oral administration. 13 week NOAEL is 100 mg/kg bw/d.

Executive summary:

In a subchronic toxicity study lactide (18:1 mixture of l-lactide and m-lactide) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 4, 20, 100 mg/kg bw/day for 13 weeks.

The only apparent toxic effect at 100 mg/kg/day was gastrointestinal irritation. Therefore, the local LOAEL is 100 mg/kg/d. No systemic effects were reported at 100 mg/kg/d. Thus, the systemic NOAEL for orally administered lactide under the conditions in this study was considered to be 100 mg/kg/day.

This subchronic study in dog is acceptable and satisfies the principle requirement for a subchronic oral study similar to OECD 409 in dog.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Lactide is rapidly hydrolysed to lactic acid in water and in-vivo (gastric acid). Lactic acid is a ubiquitous and essential molecule of life. Lactate is non-toxic, any (local) effects are due to pH effects only.

In addition, in an oral toxicity (dose range finding) study, lactide (18:1 mixture of l-lactide and m-lactide) was administered to beagle dogs by capsule at dose levels of 10, 100, 400, 1.000 and 2.500 mg/kg bw/day for 2 weeks, and 0, 4, 20 and 100 mg/kg/d for 13 weeks. The primary toxic effect of lactide in dogs was irritation of the alimentary tract. As irritating effects occurred down to a daily dose of 400 mg/kg bw (for 2 wks), the sub-chronic study was run with a maximum dose of 100 mg/kg bw/d.

At 1.000 and 2.500 mg/kg/d effects on body weight, and absolute and relative organ weights were reported in the 14 -day dose range finding study for thymus and spleen. These effects were considered secondary to the irritation of the alimentary tract. In addition, a mild to moderate renal tubular regeneration was reported in all animals of the 2.500 mg/kg/d dose. Regeneration of the renal tubular epithelium is frequently seen as a reparative or adaptive change following tubular epithelial necrosis, and is suggestive of prior damage to this tissue. Although the mechanism of this effect is unknown, lactide toxicity cannot be excluded. Based on the possible renal toxicity the (systemic) LOAEL is 2.500 mg/kg bw/day. That's well above the Limit Dose of 1.000 mg/kg/d for a sub-acute toxicity study.

No systemic adverse effects were reported at the highest dose tested in the 90 d study (100 mg/kg/d). Therefore, the (systemic) NOAEL for orally administered lactide in a 90d study in dog is considered to be 100 mg/kg/day. The primary toxic effect after oral dosing was irritation of the gastrointestinal tract at 100 mg/kg/d.

Justification for classification or non-classification

L-lactide is to be considered non-toxic; the only effect are due to local irritation in the gastrointestinal tract as a consequence of the formation of lactate derivatives including lactoyl lactic acid and monomeric lactic acid. Therefore, based on the available data L-lactide does not warrant classification for repeated dose toxicity.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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